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P3‐308: Characterization of amino‐terminally truncated Abeta‐42 peptides in plasma from Alzheimer's patients receiving solanezumab immunotherapy treatment
Author(s) -
DeMattos Ronald B.,
Racke Margaret,
Gelfanova Valentina,
Knierman Michael,
Hale John,
Dean Robert,
Paul Steven,
Siemers Eric
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1809
Subject(s) - peptide , amino acid , chemistry , urea , peptide sequence , immunoprecipitation , amyloid (mycology) , biochemistry , microbiology and biotechnology , biology , inorganic chemistry , gene
also assessed the specificity of E2012 for different gamma-secretase substrates. Results: E2012 was shown to decrease Ab(x-40) and Ab(x-42) and to increase Ab(1-38) without changing total Ab(1-x) levels. MALDITOF analysis also revealed that E2012 reduced Ab40 and Ab42 and increased shorter Ab peptides, such as Ab37 and Ab38. E2012 did not induce the accumulation of APP-CTFs, suggesting that E2012 modulates, but does not inhibit, the cleavage of APP-CTF by gamma-secretase. Production of Notch intracellular domain (NICD) was not inhibited by E2012. Conclusions: We have profiled E2012, a compound from a new chemical class of GSMs, and found that it preferentially reduced gamma-secretase mediated Ab40 and Ab42 production over Notch cleavage via a different mechanism from that of classical GSIs. These results provide the basis for the development of E2012 as a new therapeutic agent for Alzheimer’s disease.